Discussion:
In the present study, we investigated the expression of CCR5 in samples from UC. We compared the expression levels in those samples to levels from tissue samples of other common tumors known to express high levels of CCR5 using an inhibitor-based IHC assay. To our knowledge, this is the first report of high levels of expression of CCR5 protein in UC in comparison to other tumors. With the maturation of CCR5 as a therapeutic target, our results may have clinical applications in treating this disease. The CCR5 is a G protein-coupled receptor belonging to the beta chemokine receptors family of integral membrane proteins predominantly seen on T cells, macrophages, dendritic cells, eosinophils, microglia, and a subpopulation of breast or prostate cancer cells10. Recent studies indicate that CCR5 inhibitors blocked the migration and metastasis of breast and prostate cancer cells that expressed CCR511,12. Sicoli et al. examined the molecular mechanisms governing prostate cancer bone metastasis by tranducing FVB murine prostate epithelium with oncogenic v-Src. These prostate cancer cell lines metastasized in FVB mice to brain and bone. Sicoli et al’s - gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cells lines were grown in vivo vs. tissue cultures. The authors were then able to reduce the whole body, bone and brain metastatic prostate cancer burden by oral CCR5 antagonist. Other studies suggested that CCR5 is expressed in some cancer stem cells, which are known to drive therapy resistance, and that CCR5 inhibitors may enhance the cancer response to chemotherapy. There is very little literature investigating the association between UC and CCR5 variations. A few authors examined the effects of polymorphism in the genes encoding for CCR5 and the risk of UC in different populations. Kucukgergin et al. genotyped 142 histologically confirmed BC patients and 197 controls and demonstrated a positive association between CCR5?32 gene polymorphisms and BC risk. The frequency of the heterozygous wt/?32 genotype of CCR5 was more prevalent in BC patients than in controls14. Also, previously, genetic variants in CCR5 (CCR5wt/?32 andCCR5?32 alleles) were reported to confer a significantly high risk for early-onset smoking-related tumors. Srivastava et al. examined CCR5 ?32 polymorphism in conferring genetic susceptibility to GBC. They found that such polymorphism was associated with gallbladder cancer, particularly in patients with early-onset and tobacco usage15. This a finding which bears significance since smoking is the number one risk factor for the development of BC. Our results, if validated, may have therapeutic implications. CCR5 inhibitors have been shown to block metastasis of breast and prostate cancer. Velasco-Velázquez et al. conducted microarray analysis on 2,254 human breast cancer specimens and found increased expression of CCR5 in the basal and HER-2 genetic subtypes. The authors then showed that the CCR5 antagonists maraviroc or vicriviroc, developed to block CCR5 HIV coreceptor function, reduced in vitro invasion of basal breast cancer cells, and maraviroc decreased pulmonary metastasis in a preclinical mouse model of breast cancer. Velasco-Velázquez et al. then concluded that CCR5 antagonists might be used as an adjuvant therapy to reduce the risk of metastasis in patients with the basal breast cancer subtype11. The current study used an assay based on a diagnostic version of PRO140, a CCR5 humanized monoclonal antibody against CCR5 that, in pharmacologic form (leronlimab), showed proven efficacy and safety profile. A sub-Q injection form of PRO 140 was tested as monotherapy in HIV-1. It was generally well tolerated relative to placebo and demonstrated potent and prolonged CCR5 blocking activity when administered weekly or every other week16. Therefore, CCR5 inhibitors such as Leronlimab, Maraviroc, and Bristol Myers Squibb BMS-813160 may be potential therapeutic options for patients with UC. Patients may also benefit from a combination of CCR5 inhibitors with currently approved systemic treatment for UC. Functional CCR5 was highly expressed by tumor infiltrating Treg, and CCR5 high Treg was previously shown to be more suppressive than their CCR5 low Treg counterparts17. Therefore, blockade of CCR5 on regulatory T cells (Treg) in combination with PD-L1 blockade could reduce the Treg suppression of CD8 cells and allow the anti-tumor activity of CD8 cells to endure in patients with BC treated with PD-L1 inhibitors such as pembrolizumab and Nivolumab. Also, since CCR5 is expressed on stem-like cancer cells, CCR5 inhibitors may potentiate the response to chemotherapy in the basal type of BC that is generally unresponsive to immunotherapy and thus resembles the basal type of breast cancer
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